Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF.
Interleukin-6 (IL-6) shares several biologic properties with IL-1, including hematopoietin-1 activity and stimulation of T cells. Because many of their biologic activities overlap, we developed and used a specific radioimmunoassay (RIA) for IL-6 to compare production of this cytokine on a molar basis with that of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF)alpha. The RIA correlated well with the hybridoma bioassay for IL-6 (r = .87, P less than .001). Freshly isolated human peripheral blood mononuclear cells (PBMC) cultured in the absence of stimuli did not produce IL-6 in most cases. Kinetics of secretion and cell-association of IL-6 were studied. In contrast to IL-1 alpha but similar to TNF, IL-6 was almost entirely secreted into the extracellular fluid. Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6. However, on a molar basis PBMC produced approximately two to three times less IL-6 than IL-1 alpha, IL-1 beta, or TNF, regardless of the stimulus. The amount of IL-6 produced from PBMC was consistent when measured in the same subjects six time during a 12-week period. In a cohort of 38 donors, the coefficient of variation for IL-6 production was .32, compared with .92 for IL-1 beta and .96 for TNF. Comparing cytokine production by PBMC, there was a significant correlation between IL-6 and IL-1 beta (r = .72) and between IL-6 and TNF (r = .66). IL-6 did not stimulate IL-1 beta or TNF production, but suppressed IL-1 beta and TNF production induced by LPS or PHA by 30% (P less than .01). This suppression of IL-1 beta and TNF by IL-6 appears to be on the level of transcription.
Schindler
R
R
Department of Medicine, Tufts University School of Medicine, Boston, MA.
Mancilla
J
J
Endres
S
S
Ghorbani
R
R
Clark
S C
SC
Dinarello
C A
CA
D001681:Biological Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011863:Radioimmunoassay; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha